Efficacy of percutaneous ethanol injection therapy (PEIT) is related to the number of parathyroid glands in haemodialysis patients with secondary hyperparathyroidism.

BACKGROUND: Percutaneous ethanol injection therapy (PEIT) is used for advanced secondary hyperparathyroidism. We investigated the efficacy, remission period and risk of relapse to determine the effect of the number of hyperplastic glands and other factors on the therapeutic effect of PEIT. METHODS: We studied 321 patients divided into two groups: effective [serum corrected calcium (cCa) level < or =10.5 mg/dl and serum intact parathyroid hormone (iPTH) level < or =250 pg/ml], and ineffective (failed to achieve the target levels). Advanced hyperplasia was defined as an estimated volume > or =0.5 cm(3) on ultrasonography. RESULTS: PEIT was effective in 201 patients (62.6%), in whom serum iPTH levels dropped from 603+/-292 to 183+/-62 pg/ml (ng/l) and serum cCa levels from 10.7+/-0.8 to 10.1+/-0.5 mg/dl. Univariate analysis identified age, the number of hyperplastic glands and iPTH level as factors related to the efficacy of PEIT. The odds ratio for success vs failure by multivariate analysis was 0.55 times for the number of hyperplastic glands > or =0.5 cm(3) (> or =2 vs 0,1) and 0.29 times for iPTH (> or =500 vs <500 pg/ml). Using the Kaplan-Meier method, the number of hyperplastic glands > or =0.5 cm(3) (> or =2 vs 0,1) was a factor affecting the remission period, with a remission significantly longer seen in the group with one hyperplastic gland (P=0.0025). CONCLUSIONS: Superior results in efficacy rate, remission period and risk of relapse are obtained when PEIT is restricted to patients with one hyperplastic gland > or =0.5 cm(3).     

Percutaneous ethanol (PEIT) and calcitrol (PCIT) injection therapy are ineffective in treating severe secondary hyperparathyroidism.

BACKGROUND: Secondary hyperparathyroidism (2HPT) is a frequent complication of long-term dialysis treatment and, despite recent advances in medical therapy, surgical parathyroidectomy (PTX) is required in a considerable number of uraemic patients. Recently, other modalities of therapy, such as ultrasound-guided percutaneous parathyroid injection of ethanol (PEIT) or of calcitriol (PCIT), have been used to treat refractory 2HPT. Our objectives were to evaluate the efficacy of these therapeutic modalities and to analyse their effects on parathyroid cell proliferation. METHODS: Nineteen haemodialysis patients with severe 2HPT were studied. Ten underwent PEIT (Group I) and nine underwent PCIT (Group II). After treatment, five patients in each group were submitted to PTX. Parathyroid cell proliferation was appraised at the beginning and at the end of the study by fine-needle aspiration biopsy, making use of immunocytochemical testing for Ki-67. The surgically removed glands were submitted to histopathological analysis and cellular proliferation was evaluated. RESULTS: Both PEIT and PCIT proved inefficient in controlling 2HPT. Comparing study onset with day 60, both groups showed a significant decrease in serum-ionized calcium: 5.3+/-0.3 vs 5.1+/-0.5 mg/dl (P = 0.03) in Group I and 5.5+/-0.4 vs 5.4+/-0.3 mg/dl (P = 0.03) in Group II. Other laboratory parameters were unchanged. There was a significant, although transitory, enlargement in glandular volume in Group II at day 30 when compared with study onset (1.5+/-0.6 vs 1.7+/-0.7 cm(3), P = 0.02). When comparing the two groups, Group I showed a glandular volume smaller than that of Group II at days 30 (1+/-0.5 vs 1.7+/-0.7 cm(3), P = 0.003), 60 (0.8+/-0.4 vs 1.5+/-0.9 cm(3), P = 0.006) and 90 (0.8+/-0.5 vs 1+/-0.7 cm(3), P = 0.02). Cellular proliferation, which was equally elevated in both groups at the beginning of the study, could not be evaluated at the end due to lack of material. The majority of glands obtained through PTX presented intensive cellular proliferation and contained areas of nodular hyperplasia, even those glands with a volume of <0.5 cm(3). CONCLUSION: In our experience, both PCIT and PEIT were unable to control severe 2HPT in chronic haemodialysis patients. We believe that the severity of the 2HPT in the study patients, in conjunction with the fact that we excluded from treatment parathyroid glands with a volume of <0.5 cm(3), were the most important causes of this failure.     

Ultrasound-guided percutaneous fine-needle ethanol injection into parathyroid glands in secondary hyperparathyroidism.

To reduce parathyroid hormone concentrations in uraemic patients refractory or hyporesponsive to calcium supplements and active metabolites of vitamin D, we developed in 1982 a new parathyroid ablative technique consisting of percutaneous fine-needle ethanol injection (PFNEI) into enlarged parathyroid glands under ultrasonic guidance. Fifty uraemic patients have been treated. Decreases in carboxy terminal parathyroid hormone (PTH) were 50% or more in 13 of 50 patients followed up (26%) at 1 month, in 13 of 48 (27%) at 6 months, and in 9 of 25 (36%) at 12 months. Decreases of 30% or more in PTH were obtained in 21 of 50 (42%), in 25 of 48 (52%), and in 15 of 25 (60%). In 'responsive' patients, serum total alkaline phosphatase was significantly reduced [from 579 +/- 645 U/l to 360 +/- 354 U/l (P less than 0.01) at 6 months, and to 273 +/- 311 U/l (P less than 0.01) at 12 months] and bone isoenzyme decreased similarly [from 482 +/- 608 U/l to 256 +/- 344 U/l (P less than 0.005), and to 225 +/- 354 U/l (P less than 0.01)]. The best results were in seven patients who had relapsed after subtotal parathyroidectomy. Declines in PTH of 30% or more were observed in four of seven patients at 1 month, in six of the seven (85%) at 6 months, and in all four patients seen after 12 months. The treatment corrected hypercalcaemia, making it possible to start or to increase daily vitamin D treatment. Side-effects were mild, rare, and transient.     

Effects of percutaneous ethanol injection therapy on subsequent parathyroidectomy

BACKGROUND: Although percutaneous ethanol injection therapy (PEIT) is an alternative to surgery for patients with secondary or tertiary hyperparathyroidism, it also has been conjectured to make subsequent parathyroidectomy more difficult. METHODS: The records of 37 patients with end-stage renal disease managed between September 2000 and August 2005 were reviewed retrospectively. All patients had hyperparathyroidism intractable to medical treatment, and all eventually underwent parathyroidectomy. Of the 37 patients, 20 initially underwent PEIT, whereas 17 did not. Surgical and biochemical outcomes were compared between the 2 groups. RESULTS: i-PTH and biochemical markers before and after surgery did not differ significantly between the 2 groups, nor did the outcome, defined as persistent hypocalcemia, persistent hyperphosphatemia, persistent low or high i-PTH, persistent hoarseness, or residual parathyroid mass. Parathyroidectomy in the PEIT group proceeded smoothly and was not hindered by inflammation or tissue adhesion. CONCLUSIONS: Using PEIT to treat hyperparathyroidism in patients with end-stage renal disease does not make subsequent parathyroidectomy more difficult.     

A case of post-transplant hyperparathyroidism treated with ethanol injection

A 15-year-old boy with chronic renal failure secondary to Alport’s syndrome underwent living-related renal transplantation from his 48-year-old father. His primary immunosuppressive regimen was composed of tacrolimus, mizolibine, and methylprednisolone. The postoperative course was satisfactory with one episode of mild acute rejection, treated successfully with methylprednisolone pulse therapy. Two months later, hypercalcemia (11.8–13.2 mg/dl) and hypophosphatemia (2.5–3.0 mg/dl) were noted without any bone symptoms. The serum intact-parathyroid hormone (PTH) and serum alkaline phosphatase levels were 240 pg/ml and 2483 IU/l, respectively. Ultrasound studies revealed enlargement of the two parathyroid glands. Under the diagnosis of ter-tiary hyperparathyroidism, he underwent percutaneous ethanol injection (PEIT) into the left parathyroid gland. Although levels of serum calcium and phosphorus returned to normal ranges and the intact PTH level decreased to 95 pg/ml with the three injections, another injection was needed to normalize recurrent hypercalcemia 2 months later. The patient experienced only transient mild dysphonia and local pain after PEIT. Although PEIT is believed less effective than parathyroidectomy, it has some advantages such as applicability to high-risk patients, repeatability of treatment, low incidence and severity of side effects. Received: 26 June 2001 / Revised: 21 November 2001 / Accepted: 24 November 2001     

A child with adrenocortical carcinoma who underwent percutaneous ethanol injection therapy for liver metastasis

The authors encountered a 2-year-old-girl with adrenocortical carcinoma who underwent percutaneous ethanol injection therapy (PEIT) for liver metastasis. The patient had functional adrenocortical carcinoma diagnosed and underwent excision of the tumor in the right adrenal gland. Because liver metastasis was detected 11 months after surgery, the patient underwent PEIT under general anesthesia. After the treatment, the size of the metastatic tumor was reduced with calcification and then disappeared. The patient was in a good condition 3 years, 3 months after the occurrence of liver metastasis.     

Intermittent high-dose oral 1,25-dihydroxyvitaimin D3 for secondary hyperparathyroidism in hemodialysis patients

We attempted to confirm whether intermittent high-dose oral 1,25-dihydroxyvitamin D₃ (PULSE) suppressed parathyroid hormone (PTH) secretion, inhibited parathyroid cell proliferation, and increased bone mass in uremic patients (Pts). Twenty two long-term hemodialysis Pts with secondary hyperparathyroidism were given 3.4±0.8μg 1,25 dihydroxyvitamin D₃ twice a week for 9.5±3.3 M. The size of parathyroid gland (PT) was estimated by echography and computed tomography every 3 months. Bone mineral density of the radius (BAD) was measured by single photon absorptiometer (Norland SPA 26). Findings were:

Evolution of secondary hyperparathyroidism after renal transplantation

Renal osteodystrophy is an important problem in children with chronic renal failure, leading to skeletal deformities. The most-frequent type of renal osteodystrophy is secondary hyperparathyroidism, and the main factors contributing to the pathogenesis of this condition are completely or partially corrected after successful renal transplantation. The present paper reviews data on the evolution of secondary hyperparathyroidism after transplantation. Studies in both adults and children suggest that secondary hyperparathyroidism and increased bone remodelling activity may persist months after transplantation. The severity of secondary hyperparathyroidism prior to transplantation, the duration of dialysis, and the development of nodular and/or monoclonal hyperplasia of parathyroid glands are the most-important factors that determine the phenomenon. Important issues, which still need to be answered, are the possible roles of growth factors, cytokines, VDR gene polymorphism (B/b allele), and type of immunosuppressive regimen in the skeletal abnormalities observed. Received: 16 April 1999 / Revised: 27 September 1999 / Accepted: 5 October 1999     

Bone scan of hemodialysis patients with secondary hyperparathyroidism before and after parathyroidectomy

Renal osteodystrophy (ROD) accompanied by long-term hemodialysis patients with chronic renal failure includes several forms of disorders of mineral and skeletal metabolism such as osteitis fibrosa attributed to secondary hyperparathyroidism, osteomalasia and adynamic bone disease. Bone scan is performed to detect of the mainly pathophysiology of ROD. We investigated bone scan of 25 hemodialysis patients with secondary hyperparathyroidism diagnosed clinically before and after parathyroidectomy (PTX). Before PTX an diffusely high accumulation of bone seeking agent in the whole skeleton especially skull in all patients (100%), vertebra in 24 out of 25 (96%), patella in 24/25 (96%), limbs in 23/25 (92%), sternum in 19/25 (76%), sacrum in 18/25 (72%) and costochondral junctions in 14/25 (56%) was noted in these patients. The radionuclide activity of the calvaria, maxilla and mandible in the skull was prominently high. Fourteen patients had an equally high activity in the calvaria, maxilla and mandible, 6 patients had higher activity in the maxilla and mandible than that of calvaria and 5 patients had higher in the calvaria than that of maxilla and mandible. After PTX the changes in the skull were obvious in 19 patients who showed a more markedly decreased in activity of the maxilla and mandible than that of the calvaria. In 3 patients showed a more markedly decreased in activity of the calvaria than that of the maxilla and mandible. Another 3 demonstrated equally decreased in activity in the calvaria, maxilla and mandible. It became clear that the highest activity of the skull was shown in all patients and the therapeutic changes of the skull are the most pronounced in maxilla and mandible in this study.     

Alterations in serum phosphate levels predict the long-term response to intravenous calcitriol therapy in dialysis patients with secondary hyperparathyroidism

Calcitriol therapy is a central strategy for the treatment of uremic secondary hyperparathyroidism. Although indiscriminate use of calcitriol may lead to worse outcomes, it is difficult to make a decision to discontinue calcitriol therapy when its parathyroid suppression effect remains unsatisfactory. In this study, intravenous calcitriol was administered to 120 chronic hemodialysis patients. Therapy continued for 48 weeks or until plasma intact parathyroid hormone (iPTH) levels decreased to below 300 pg/ml or until the development of any significant adverse effect. Of the 120 patients, the treatment goal was achieved in 47 patients during the first 4 weeks, in 10 during the next 4 weeks, and in 22 patients thereafter. Logistic regression analysis and stepwise regression analysis revealed that iPTH levels were the only significant predictor of the response to calcitriol therapy at weeks 0 and 4. Besides iPTH, the inorganic phosphate (P) levels were another significant predictor of the ultimate response to calcitriol therapy at week 8. The point of best discrimination for successful treatment was P = 6.0 mg/dl at week 8, or P level at week 8/pretreatment P level = 1.0. In conclusion, the P level at week 8 is a predictor of the response to calcitriol therapy for uremic secondary hyperparathyroidism. Changes in treatment are recommended if patients show unsatisfactory parathyroid suppression with a hyperphosphatemic tendency.     

Avoidance of direct injury to the peripheral nerve with maxacalcitol (22oxa-1,25(OH)2D3) in rats

BACKGROUND: Secondary hyperparathyroidism is one of the most common complications in patients with long-term end-stage renal disease. A recent report has stated that high doses of vitamin D derivatives injected directly into the parathyroid glands can reduce serum parathyroid hormone levels and suppress further enlargement of the parathyroid glands without side-effects. Maxacalcitol (22oxa-1,25(OH)(2)D(3); OCT) is a new vitamin D derivative that can be administered intravenously, and is available in Japan. Direct injection of OCT into enlarged parathyroid glands is a promising new treatment for moderate renal hyperparathyroidism. It is considered to be safe for surrounding tissues, such as peripheral nerves, but the actual effects of OCT on nerves have not yet been documented. METHODS: We measured nerve conduction velocity (NCV) in 24 rat femoral nerves soaked in saline, ethanol, or OCT at various concentrations. Nerves from each group (saline, ethanol, OCT groups) were also examined by microscopy. RESULTS: The mean NCV of rat femoral nerves was 33.67 +/- 1.39 m/s in the saline group. In the OCT group, the velocities were not changed at any of the concentrations tested, and there were no significant differences in NCVs between the saline and OCT groups. In the 50% ethanol group, the velocity decreased significantly to 8.98 +/- 4.78 m/s (P < 0.01). A histological study demonstrated the nerves soaked in OCT at 10 microg/mL to essentially be intact, while those soaked in anhydrous ethanol were damaged. CONCLUSIONS: This study demonstrated that OCT administration does not affect peripheral NCV, indicating that OCT could possibly be used for the treatment of moderate renal hyperparathyroidism safely without nerve damage.     

Intratubular calcification in a post-renal transplanted patient with secondary hyperparathyroidism

Iguchi S, Nishi S, Shinbo J, Iino N, Kazama JJ, Shimada H, Ueno M, Saitou K, Tanigawa T, Takahashi K, Gejyo F. Intra-tubular calcification in a post-renal transplanted patient with secondary hyperparathyroidism. Clin Transplantation 2001: 15 (Supplement 5): 51–54. ©Munksgaard, 2001
In this article, we present a case in which marked intratubular calcification occurred in the transplanted kidney. The patient received living renal transplantation without control of severe secondary hyperparathyroidism, and the tacrolimus hydrate was used as an immunosuppressive agent, the adverse effects of which can induce intratubular calcification. Biopsy of the renal allograft revealed many intratubular calcifications in the cortex region of the specimen, although the histological grade was borderline for the Banff classification. The pathogenic causes of intratubular calcification were difficult to distinguish from the adverse effects of tacrolimus and the uncontrolled hyperparathyroidism.     

Pathogenesis and management of hyperparathyroidism in end-stage renal disease and after renal transplantation

SUMMARY: Secondary hyperparathyroidism is an adaptive response to progressive loss of renal function so as to maintain calcium and phosphate homeostasis, 1,25-dihydroxyvitamin D₃ levels and normal bone turnover, despite skeletal resistance to parathyroid hormone. As feedback regulation fails, complications of parathyroid overactivity develop, and by the commencement of dialysis abnormal bone histology is present in almost all patients, with hyperparathyroid changes most commonly found. Post transplantation, persisting hyperparathyroidism predisposes to osteoporosis. The risk of bone disease is reduced by early, carefully targeted dietary measures and suppressive therapy with calcitriol and calcium-based phosphate binders, while newer therapies include bisphosphonates and calcimimetics. Timely surgical intervention is necessary in some patients.     

Use of calcimimetics in uremic patients with secondary hyperparathyroidism: review

Recognition of the role of the extracellular calcium sensing receptor (CaR) in mineral metabolism has greatly improved our understanding of calcium homeostasis. The activation of this receptor by small changes in extracellular ionized calcium (ec(Ca2+)) regulates PTH, calcitonin secretion, urinary calcium excretion, and ultimately, bone turnover. The cloning of this CaR and the discovery of mutations making the receptor less or more sensitive to calcium allowed a better understanding of several hereditary disorders characterized either by hyperparathyroidism or hypoparathyroidism. This CaR became an ideal target for the development of compounds, the calcimimetics, able to amplify the sensitivity of the CaR to ec(Ca2+) suppressing PTH levels with a resultant fall in blood Ca2+. The first clinical studies with first-generation calcimimetic agents have demonstrated their efficacy lowering plasma intact PTH concentration in uremic patients with secondary hyperparathyroidism. However, the low bioavailability of these first calcimimetics predicts a difficult clinical utilization. The second-generation calcimimetic AMG-073, with a better pharmacokinetic profile, appears to be effective and safe for the treatment of secondary hyperparathyroidism, producing suppression of PTH levels with a simultaneous reduction in serum phosphorus levels and the calcium X phosphorus product. The advantage of controlling PTH secretion without the complications related to hypercalcemia, hyperphosphatemia, and increased calcium X phosphorus product is very promising.     

Mobilization of lead from bone in end-stage renal failure patients with secondary hyperparathyroidism.

BACKGROUND: It is now recognized that long-term exposure to even low levels of lead may increase bone lead content. Lead can then be released in toxicologically significant amounts during critical states of increased bone turnover. METHODS: Two patients with end-stage renal failure, one on haemodialysis and the other on continuous ambulatory peritoneal dialysis (CAPD), had been exposed to lead and developed secondary hyperparathyroidism. An edetate calcium disodium (EDTA) test was performed in combination with haemofiltration or CAPD before and after parathyroidectomy. RESULTS: Before parathyroidectomy, both patients had low delta aminolaevulinic acid dehydrase (ALA-D) and high concentrations of chelated lead. After parathyroidectomy, there was a dramatic decrease in chelated lead and the ALA-D returned to normal. CONCLUSION: Secondary hyperparathyroidism increases mobilization of bone lead in dialysis patients with an elevated lead burden. This may cause toxic effects.     

Relationship between parathyroid gland size and responsiveness to maxacalcitol therapy in patients with secondary hyperparathyroidism.

BACKGROUND: Although vitamin D has been reported to be useful in the treatment of patients with secondary hyperparathyroidism, it is not effective in some of them. The goal of this study was to see whether a relationship could be found between maxacalcitol responsiveness and parathyroid gland size. METHODS: Parathyroid gland size was measured by ultrasonography in 25 patients with secondary hyperparathyroidism [serum intact parathyroid hormone (PTH) >300 pg/ml, 58.1 +/- 2.8 years old, 15 males and 10 females], who were treated with maxacalcitol. Patients were divided into two groups according to the mean value of the maximum diameter of the glands: group S with a diameter <11.0 mm and group L with a diameter >or =11.0 mm. Between the two groups there were no significant differences in serum intact PTH, calcium or phosphate level or duration of haemodialysis. RESULTS: Mean (+/- SE) maximal diameter of detectable parathyroid glands was 11.0 +/- 0.7 mm before treatment. At 4-24 weeks after administration of maxacalcitol, intact PTH concentrations decreased significantly in group S (from 546 +/- 39 to 266 +/- 34 pg/ml at 24 weeks; P < 0.01), but did not significantly change in group L (from 481 +/- 39 to 403 +/- 49 pg/ml at 24 weeks). At 24 weeks after maxacalcitol administration, the number of detectable parathyroid glands was significantly decreased in group S (from 2.2 +/- 0.3 to 1.8 +/- 0.4; P < 0.05), but not in group L. Serum calcium increased significantly in group L (from 9.6 +/- 0.2 to 10.2 +/- 0.3 mg/dl; P < 0.05), but not in group S. There was a significant correlation between reduction in PTH and parathyroid gland size (r = -0.42, P < 0.05). CONCLUSIONS: These results indicate that the responsiveness to maxacalcitol therapy of secondary hyperparathyroidism is dependent on parathyroid gland size and that the simple measurement of maximum parathyroid gland diameter by ultrasonography may be useful for predicting responsiveness to maxacalcitol treatment.     

Severe hyperparathyroidism with bone abnormalities and metastatic calcification in rats with adenine-induced uraemia.

BACKGROUND: Marked parathyroid hyperplasia with bone diseases and vascular calcification are unsolved issues in dialysis patients. In this study, we made azotemic model rats by adenine feeding and analyzed the development and progression of the abnormalities. METHODS: Renal failure was induced in 8-week-old male Wistar rats by feeding 0.75% adenine-containing diet for 6 weeks. Serum parameters, parathyroid hyperplasia, bone changes and metastatic calcification were examined at 2, 4 and 6 weeks. RESULTS: Progressive increase of serum creatinine and inorganic phosphate, and decreased levels of serum calcium and 1,25(OH)2D3 were confirmed. Markedly enlarged parathyroid glands and extremely high PTH levels were observed in all adenine-fed rats compared with the control (PTH: 199.3+/-58.0 vs 10.5+/-3.0 pmol/l, P<0.01, respectively, at 6 weeks). In cortical bone of the femur, the morphometric parameters showed increased bone resorption with increased fibrosis, whereas in the trabecular bone, bone resorption decreased and bone volume increased with a larger amount of osteoid compared with the control. Metastatic calcification in aorta, coronary artery and other soft tissues were also found in adenine-fed rats. CONCLUSIONS: Uraemic rats made by adenine diet developed severe abnormalities of calcium metabolism in a relatively short period and therefore they may serve as a useful model for the analysis of parathyroid hyperplasia and vascular calcification in chronic renal failure.     

Evaluation of parathyroid hyperplasia by ultrasonographic examination in patients with end-stage renal failure before and at initiation of dialysis

SUMMARY:   Secondary hyperparathyroidism (2HPT), which is related to renal osteodystrophy (ROD), may occur in patients in the comparatively early stage of chronic renal failure (CRF). Secondary hyperparathyroidism patients with parathyroid hyperplasia showed resistance to vitamin D₃ treatment during long-term dialysis. At present, evaluation by ultrasonography is considered to be useful for confirming parathyroid hyperplasia. There are no clinical data associated with imaging evaluation of 2HPT in CRF patients. In the present study, the relationship among clinical and biochemical data, and parathyroid hyperplasia by ultrasonography, was evaluated in 12 patients (six males and six females) with end-stage renal failure (ESRF) before and at initiation of dialysis. Five patients showed an enlargement of parathyroid glands in ultrasonography. Levels of serum-intact parathyroid hormone (PTH) in patients with parathyroid hyperplasia (positive group) were significantly higher than in those without hyperplasia (negative group; 97.6 ± 36.65 vs 17.4 ± 4.45 pmol/L; P  < 0.05). The levels of intact PTH were above 35.0 pmol/L in all five patients with hyperplasia. All patients in the positive group had never taken vitamin D₃ supplements. Calcium-containing phosphate binders were not prescribed before the present study, except in one patient. Parathyroid hyperplasia caused by 2HPT was recognized in patients before and at initiation of dialysis in this study. It appears that untreated 2HPT in CRF patients may progress to advanced 2HPT in ESRF before and/or after the early stage of dialysis. The levels of serum intact PTH are useful in predicting parathyroid hyperplasia.